New Alzheimer's Gene Discovered

One of only two genes with a known connection to the most common form of the disease, SORL1 may lead researchers to new treatment options

by Catherine Arnst

Researchers have discovered a second gene implicated in late-onset Alzheimer's disease, which sets in after age 65 and is the most common form of the disease. The discovery provides both a new drug development target and further evidence that scientists are on the right track in seeking medicines that will combat the disease. Currently, there are no drugs that will slow or reverse the brain cell death caused by Alzheimer's.

Scientists have been intensively searching for genes related to Alzheimer's for decades with little success. The first major gene for late-onset Alzheimer's, APOE, was discovered 14 years ago. Other genes have been linked to the early-onset form of the disease, which strikes before age 60 and accounts for only 10% of all cases.

A team of researchers from Boston University, the University of Toronto, and Columbia University spent five years locating the newly discovered gene, called SORL1, using DNA samples from more than 6,000 volunteers from four distinct ethnic groups. Dr. Sam Gandy, a neuroscientist who chairs the Alzheimer's Assn.'s medical and scientific advisory council, says SORL1 probably does not play as important a role in the development of the disease as APOE, "but it does dovetail with the main hypothesis for how Alzheimer's starts. It tells us we are on the right track with drug discovery efforts."

Targeting Amyloid Plaques

Most of those efforts are aimed at blocking sticky deposits of plaque in the brain formed from a protein called amyloid. The cause of Alzheimer's, which afflicts 1 in 10 people over 65, is unknown, but many scientists believe that the amyloid plaque plays a leading role in destroying brain cells. Currently more than 60 drugs are in clinical trials for Alzheimer's, and most of these drugs aim to block or remove amyloid in the brain.

The scientists who discovered the SORL1 gene, described in the journal Nature Genetics, say that when it is working normally it plays a key protective role by recycling amyloid through the brain, preventing it from stalling and turning into toxic plaque. This protection declines in patients with a defective SORL1 gene, resulting in accumulation of amyloid in the brain.

Increased Risk

To make sure any gene they found was widespread throughout the human population—as Alzheimer's is—the researchers screened four ethnic groups: North American and European Caucasians, African Americans, Caribbean Hispanics, and Israeli Arabs. The researchers targeted groups known for having particularly high rates of Alzheimer's—thus indicating a genetic link—such as elderly residents of an Arab community in Northern Israel and Caribbean Hispanics from the Dominican Republic.

Having a defect in the SORL1 gene does not guarantee that a patient will develop Alzheimer's, but it does increase the risk. Researchers continue to search for other genetic variants linked to the disease, and there could be 20 or more. Dr. Richard Mayeux, co-director of Columbia's Taub Institute for Research on Alzheimer's Disease, says the importance of this latest discovery "is that it opens new pathways to explore the cause as well as potential targets for treatment of this devastating disease."

About 4.5 million Americans are currently diagnosed with Alzheimer's, an incurable disease that slowly destroys the patient's brain and always ends in death. The prevalence of the disease is expected to double over the next 25 years as the population ages.

Arnst is a senior writer for BusinessWeek in New York.